The British vote to leave the European Union buoyed those who question the unity of the bloc and Britain, roiled global markets, triggered the premier's resignation and prompted European populists to call for similar polls as talk of Scottish and Northern Irish independence resurfaced.
The vote comes at a time when the EU is dealing with internal tensions about its migration crisis, high unemployment and growing anti-EU sentiments among the European public.
The mostly Conservative Vote Leave platform and the right-wing UK Independence Party (UKIP) had lobbied for a so-called Brexit, arguing that this was the only way to protect Britain's sovereignty and control EU migration.
"Let June 23 go down in our history as our independence day," UKIP leader Nigel Farage said.
Leave won 52 per cent of the vote and Remain won 48 per cent, marking the first time that a country has decided to leave the EU.
The biggest effect from the referendum was that other countries were starting to doubt the EU, Farage said.
Indeed, other populist eurosceptic parties in Europe heralded the Brexit vote as an argument for holding their own anti-EU referendums.
"As I have called for years, there should now be such a referendum in France and in the countries of the EU," said Marine Le Pen, leader of France's National Front.
EU leaders said that will not happen, trying to calm the atmosphere as financial and currency markets went into turmoil.
"Today, on behalf of the 27 leaders [of the remaining EU countries], I can say that we are determined to keep our unity as 27," EU President Donald Tusk said.
Foreign ministers of the EU's founding nations are set to discuss the issue in Berlin on Saturday, followed by Tusk's separate meetings with French President Francois Hollande and German Chancellor Angela Merkel early next week.
The 27 leaders will meet at a summit in Brussels next week, Tusk said, adding that he would push for a wider reflection on the bloc's future.
EU members should "analyse the situation and make decisions in a calm and collected manner," Merkel said.
Prime Minister David Cameron announced he would resign by October, and that his successor would launch the divorce process from the EU.
"I will do everything I can as prime minister to steady the ship over the coming weeks and months, but I don't think it would be right for me to try to be the captain that steers our country to its next destination," he said.
Cameron had fought for remaining in the EU by arguing that a Brexit would hurt Britain's economy. He faced off with Brexit supporters from within his own Conservative Party.
British Foreign Secretary Philip Hammond said the government would try to keep as many trade ties with the world's largest economic bloc as possible, as Britain renegotiates its relationship with the EU.
But he warned that the Brexit vote had already made Britain a "semi-outsider" with considerably diminished diplomatic weight.
President Barack Obama said that both the EU and Britain will remain "indispensable partners" of the United States.
"The people of the United Kingdom have spoken, and we respect their decision," Obama said, noting the "special relationship" between the US and Britain and pointing to its role as a NATO ally.
Obama spoke with Cameron and German Chancellor Angela Merkel about the vote and the need to coordinate to ensure the stability of the global financial ssytem.
But signs of potential trouble ahead were already surfacing. The head of the Scottish regional government announced that Scotland would fight to stay in the EU and would therefore start preparing for a new vote on independence from Britain.
"I want to make it absolutely clear today that I intend to take all possible steps and to secure our continuing place in the EU and in the single market," Scotland's First Minister Nicola Sturgeon said.
Irish nationalist party Sinn Fein said the British government had "forfeited any mandate" to represent the interests of Northern Ireland.
Scotland and Northern Ireland overwhelmingly voted for remaining in the EU.
Most areas of England returned large majorities for Leave, except for the London area an some other southern regions.
A YouGov survey among 5,000 voters showed that, among those with a standard school education, 66 per cent voted for Brexit, while 71 per cent of those with university degrees cast pro-EU ballots.